A general synthetic strategy and preliminary investigations of pro-drug Silibinin conjugates

Silibinin is the major component of an extract, known as Silymarin, obtained from the seeds of the milk thistle (Silybum marianum). Structurally, Silibinin is diastereoisomeric equimolar mixture of two flavonolignans (Silybin A and Silybin B). As extensively reported in literature, Silibinin displays multiple biological activities, most of them related to its radical scavenging activity. In the past two decades, in addition to hepatoprotective effects, Silibinin has demonstrated remarkable anti-cancer as well as cancer chemopreventive efficacy in pre-clinical cell culture and animal models of several epithelial cancers, including skin, bladder, colon, prostate, and lung [2]. Oral administration of chemotherapeutic agents is the mainstay for the treatment of disease. Sustained release formulations have been crucial for the safe and effective dosing of orally administered drugs [3]. In this frame, the synthesis of phosphodiester derivatives can improve the oral bioavailability of poorly water-soluble metabolites maintaining their pharmacologic activity [4,5]. Here, we reported the synthesis of new Silibinin conjugates with 3'-ribonucleotide units. The phosphodiester junction is typically used in pro-drug strategies, in which the phosphate group is susceptible to hydrolysis by endogenous phosphatases, allowing the release of the active compound. The new conjugates were prepared in few steps and in good yields, starting from the suitable Silibinin or Silybin building blocks and nucleotide phosphoramidites. All compounds were full characterized by NMR and Maldi-TOF and their serum stability was evaluated by HPLC analyses.